Insights into the molecular roles of heparan sulfate proteoglycans (HSPGs—syndecans) in autocrine and paracrine growth factor signaling in the pathogenesis of Hodgkin’s lymphoma

Abstract

Syndecans (SDC, SYND) comprise a group of four structurally related type 1 transmembrane heparan sulfate proteoglycans (HSPGs) that play important roles in tumorigenic processes. SDCs exert signaling via their protein cores and their conserved transmembrane and cytoplasmic domains or by forming complexes with growth factors (GFs). In classical Hodgkin's lymphoma (cHL), a lymphoid neoplasm of predominantly B cell origin, SDC1 and SDC4 are the active SDCs, and a number of GF (vascular endothelial growth factor, fibroblast growth factor, etc.) signaling pathways have been studied. However, despite extensive pre-clinical and clinical research on SDC-mediated GF signaling in many cancer types, there is very limited data for this interaction in cHL. Thus, this review highlights the relevant literature focusing on the potential interactions of SDCs and GFs in cHL pathogenesis. Also discussed are the pre-clinical and clinical studies targeting signaling through these pathways.

Structures and interactions of syndecans

“…Syndecans play numerous biological roles, which have been previously reviewed . Their major roles are thus only briefly mentioned in this paragraph, which highlights the most recent findings.…”

Modulation of Microenvironment Signals by Proteolytic Shedding of Cell Surface Extracellular Matrix Receptors

“…Syndecans are type 1 transmembrane heparan sulfate proteoglycans (HSPGs). The heparan sulfate (HS) chains at the extracellular domains interact with different ligands, including ECM glycoproteins, cytokines, chemokines, and growth factors ( Couchman et al, 2015 ; Gharbaran, 2016 ; Afratis et al, 2017 ; Gondelaud and Ricard-Blum, 2019 ). There are four syndecans 1–4.…”

“…Syndecan core proteins are 33 kDa for syndecan-1, 23 kDa for syndecan-2, 43 kDa for syndecan-3, and 22 kDa for syndecan-4. Each syndecan is attached by three HS chains, and syndecan-1 and syndecan-3 are attached by other two chondroitin sulfate chains ( Figure 2B ; Couchman et al, 2015 ; Gharbaran, 2016 ; Afratis et al, 2017 ; Gondelaud and Ricard-Blum, 2019 ). The transmembrane domain of all syndecans contains a GXXXG motif that promotes the formation of SDS (sodium dodecyl sulfate)-resistant homo-dimers ( Choi et al, 2005 ; Dews and Mackenzie, 2007 ), and this transmembrane domain-mediated homo-dimerization has been reported to be crucial for the function of syndecan-2 and syndecan-4 ( Choi et al, 2005 ).…”

Proteoglycans in normal physiology and carcinogenesis

“…Состав и структура ГСПГ подвергаются значитель-ным изменениям в опухолях яичников и молочной железы человека [46,47]; экспрессия синдекана 1, де-корина и люмикана значительно изменяется в опухолях молочной железы [48], глипиканы вовлечены в процесс канцерогенеза в тканях легкого [49] и поджелудочной железы [50]; синдеканы участвуют в патогенезе лимфомы Ходжкина [51]; экспрессия перлекана и серглицина значительно снижается в клетках лимфомы Беркитта [52]; уровень экспрессии коллагена 18 ассоциируется с прогрессированием и прогнозом гепатоцеллюлярной карциномы [53], а в опухолях прямой кишки проис-ходит одновременное снижение уровней экспрессии декорина и перлекана (в 2 раза) и повышение экспрес-сии бигликана и версикана (в 6 и 3 раза соответственно) [54]. ПГ глипиканы, агрин, версикан и декорин при-нимают активное участие в развитии злокачественных [55].…”